Paper Session I-C - Rubicon System for Space Shuttle Vehicle Health Management

The Rubicon (Reasoning Based on Intelligent Computing and Networking) project attempts to do this by providing a vehicle for practical introduction of advanced diagnostic software into an operational environment. Rubicon takes the form of a workstation-based software system giving the engineer access to an array of vehicle health management software and data analysis tools. Rubicon includes graphical user interfaces and controls for advisory system operation and a set of utilities for real time data analysis and display. The engineer can conveniently access a powerful set of fault analysis tools at a single location. Rubicon is being developed by NASA / TV-GDS and Rockwell / Launch Support Services at KSC. It is a step toward operational vehicle health management. Rubicon demonstrates several important points. It shows that multiple advisory systems can run cooperatively on a single workstation. Also, common functions supplied by Rubicon can preclude the need for their redevelopment for future advisory systems. Finally it is possible to automate data analysis tasks that are now performed manually. When completed it will serve as a new data resource for the firing room engineer

Structure and dynamics of deep-seated slope failures in the Magura Flysch Nappe, outer Western Carpathians (Czech Republic)

International audienceDeep-seated mass movements currently comprise one of the main morphogenetic processes in the Flysch Belt of the Western Carpathians of Central Europe. These mass movements result in a large spectrum of slope failures, depending on the type of movement and the nature of the bedrock. This paper presents the results of a detailed survey and reconstruction of three distinct deep-seated slope failures in the Raca Unit of the Magura Nappe, Flysch Belt of the Western Carpathians in the Czech Republic. An interdisciplinary approach has enabled a global view of the dynamics and development of these deep-seated slope failures. The three cases considered here have revealed a complex, poly-phase development of slope failure. They are deep-seated ones with depths to the failure surface ranging from 50 to 110m. They differ in mechanism of movement, failure structure, current activity, and total displacement. The main factors influencing their development have been flysch-bedrock structure, lithology, faulting by bedrock separation (which enabled further weakening through deep weathering), geomorphic setting, swelling of smectite-rich clays, and finally heavy rainfall. All of the slope failures considered here seem to have originated during humid phases of the Holocene or during the Late Glacial

Our first clinical experience with radiosynoviorthesis by means of 166Ho-holmium-boro-macroaggregates

BACKGROUND: In this paper, we evaluate the therapeutic and adverse effects of the application of 166-holmium-boro-macroaggregates (HMBA) in radiosynovectomy (RSO) of the knees. We assessed the efficacy and safety of 166Ho-HBMA in a prospective clinical trial in patients suffering from chronic synovitis. MATERIAL AND METHODS: An effective component of radiopharmaceutical 166Ho-boro-macroaggregates is radionuclide 166Ho which has both β-emission and γ-emission. The physical half-life time of 166Ho is 26.8 hours. After application of the radiopharmaceutical into a joint cavity, the effect of β-emission causes radiation necrosis of pathologically changed (inflamed) synovial membrane. From 15th April 2005, we have started RSO of knees by means of new radiopharmaceutical 166Ho-boro-macroaggregates in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, gout arthropathy. Seventeen intra-articular injections were performed in fifteen patients receiving a mean activity of 972 MBq (range: 904-1057 MBq) 166Ho-HMBA. The patients were hospitalized for three days. Side effects were evaluated during hospital stay and after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks. RESULTS: In 2 hours and 2 days after application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in four patients. In treated patients, no serious adverse effects occurred. Nine patients were without complaints; 4 patients had slight knee exsudation and 2 patients had great exsudation. Therapeutic effects after 6-8 weeks were as follows: 2 patients were without pain, 9 with lower pain, 3 with the same pain and 1 patient with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients and greater in 1 patient. Knee exsudation was absent in 2 patients, lower in 4 patients, the same in 6 patients and greater in 3 patients. CONCLUSIONS: We proved only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes. Six patients had early slight or great radiation synovitis. The possible cause could be rather high applicated activity. One can take into consideration its reduction. Therapeutic effects can be precisely evaluated after a longer time interval than was possible for us (6-8 weeks after RSO). 166Ho-boro-macroaggregates can extend the scale of clinically used radiopharmaceuticals for RSO. This paper is presented in the scope of the first stage of clinical evaluation of synovectomy application of holmium-boro-macroaggregates

Increased Urinary Nitrate Excretion in Inflammatory Bowel Disease

Peer Reviewe

Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1 cm) associated with ovarian cancer or primary peritoneal carcinoma

<p>Abstract</p> <p>Background</p> <p>Pharmacokinetic advantages of intraperitoneal (IP) rhIL-12, tumor response to IP delivery of other cytokines as well as its potential anti-angiogenic effect provided the rationale for further evaluation of IPrhIL-12 in patients with persistent ovarian or peritoneal carcinoma.</p> <p>Methods</p> <p>A phase 2 multi-institutional trial (NCI Study #2251) of IP rIL-12 (300 nanogram/Kg weekly) was conducted in patients with ovarian carcinoma or primary peritoneal carcinoma.</p> <p>Patients treated with primary therapy for ovarian cancer who had no extraabdominal/parenchymal disease or bulky peritoneal disease were eligible. Four to 8 weeks from last chemotherapy, eligible patients underwent a laparotomy/laparoscopy. Patients with residual disease ≤ 1 cm were registered for the treatment phase 2–5 weeks post surgery. The effect of IP rIL-12 on the expression of TNFα , INFα , IL-10, IP-10, IL-8, FGF, VEGF was also studied.</p> <p>Results</p> <p>Thirty-four patients were registered for the first screening phase of the study. Median age was 56.6 years (range: 31–71); 12 completed the second phase and were evaluable for response/toxicity. Performance scores of IL-12 treated patients were 0 (11 pts) and 1 (1 pt). There were no treatment related deaths, peritonitis or significant catheter related complications. Toxicities included grade 4 neutropenia (1), grade 3 fatigue (4), headache (2), myalgia (2), non-neutropenic fever (1), drug fever (1), back pain (1), and dizziness (1). The best response observed was SD. Two patients had SD and 9 had PD, and 1 was evaluable for toxicity only.</p> <p>Peritoneal fluid cytokine measurements demonstrated a ≥ 3 fold relative increase post-rhIL-12: IFN-γ, 5/5 pts; TNF-α , 1/5; IL-10, 4/5; IL-8, 5/5; and VEGF, 3/5. IP10 levels were increased in 5/5 patients. Cytokine response profiles suggest either NK or T-cell mediated effects of IP rhIL-12. Cytokine/chemokine results also suggest a pleiotropic response since proteins with potential for either anti-tumor (IFN-γ , IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected.</p> <p>Conclusion</p> <p>IP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma. The maximum response was stable disease. Future IP therapies with rhIL-12 will require better understanding and control of pleiotropic effects of IL-12.</p

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

The PI3K/Akt pathway upregulates Id1 and integrin α4 to enhance recruitment of human ovarian cancer endothelial progenitor cells

<p>Abstract</p> <p>Background</p> <p>Endothelial progenitor cells (EPCs) contribute to tumor angiogenesis and growth. We aimed to determine whether inhibitors of differentiation 1 (Id1) were expressed in circulating EPCs of patients with ovarian cancer, whether Id1 could mediate EPCs mobilization and recruitment, and, if so, what underlying signaling pathway it used.</p> <p>Methods</p> <p>Circulating EPCs cultures were from 25 patients with ovarian cancer and 20 healthy control subjects. Id1 and integrin α4 expression were analyzed by real-time reverse transcription-polymerase chain reaction and western blot. EPCs proliferation, migration, and adhesion were detected by MTT, transwell chamber, and EPCs-matrigel adhesion assays. Double-stranded DNA containing the interference sequences were synthesized according to the structure of a pGCSIL-GFP viral vector and then inserted into a linearized vector. Positive clones were identified as lentiviral vectors that expressed human Id1 short hairpin RNA (shRNA).</p> <p>Results</p> <p>Id1 and integrin α4 expression were increased in EPCs freshly isolated from ovarian cancer patients compared to those obtained from healthy subjects. siRNA-mediated Id1 downregulation substantially reduced EPCs function and integrin α4 expression. Importantly, Inhibition of PI3K/Akt inhibited Id1 and integrin α4 expression, resulting in the decreasing biological function of EPCs.</p> <p>Conclusions</p> <p>Id1 induced EPCs mobilization and recruitment is mediated chiefly by the PI3K/Akt signaling pathway and is associated with activation of integrin α4.</p

Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P&lt;0.001). The objective response rate was 42% versus 27% (P&lt;0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P = 0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with = 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients